RESUMEN
Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.
Asunto(s)
Ácidos y Sales Biliares , Fibras de la Dieta , Microbioma Gastrointestinal , Inflamación , Inulina , Animales , Humanos , Ratones , Ácidos y Sales Biliares/metabolismo , Ácido Cólico/farmacología , Fibras de la Dieta/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Inmunidad Innata , Inflamación/inducido químicamente , Inflamación/clasificación , Inflamación/patología , Inulina/farmacología , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Metabolómica , Pulmón/efectos de los fármacos , Pulmón/patología , Intestinos/efectos de los fármacos , Intestinos/microbiología , Intestinos/patología , Interleucina-33/metabolismo , Eosinófilos/citología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunologíaRESUMEN
Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.